`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PHIGENIX, INC.
`Petitioner
`
`v.
`
`IMMNUNOGEN, INC.
`Patent Owner
`
`_____________________
`
`Case IPR2014-00676
`Patent 8,337,856
`_____________________
`
`DECLARATION OF GEOFFREY A. PIETERSZ, PH.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IMMUNOGEN 2134, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`
`
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I. 
`Introduction ..................................................................................................... 4 
`II.  My background and qualifications ................................................................. 5 
`III.  List of documents I considered in formulating my opinions .......................... 7 
`IV.  Person of ordinary skill in the art ................................................................. 20 
`V. 
`State of the art ............................................................................................... 21 
`A. 
`Technical background on immunoconjugates ..................................... 21 
`B. 
`Problems encountered in the immunoconjugate field ......................... 24 
`1) 
`Antigen-dependent and antigen-independent toxicity ............. 25 
`2) 
`Limitations of xenograft models .............................................. 26 
`Development of HER2 as an immunoconjugate target,
`culminating in the observation of antigen-dependent toxicity ............ 30 
`VI.  The ’856 patent ............................................................................................. 36 
`VII.  Basis of my opinion with respect to obviousness ......................................... 37 
`VIII.  Summary of my Opinion with respect to obviousness ................................. 39 
`IX.  A POSA would not have had a reason to conjugate Herceptin® and a
`maytansinoid to make an immunoconjugate because of toxicity concerns. 42 
`A.  A POSA would
`have
`expected
`an
`anti-HER2
`immunoconjugate to have unacceptable levels of antigen-
`dependent toxicity ............................................................................... 43 
`In vivo rodent and in vitro testing would not have predicted
`antigen-dependent toxicity .................................................................. 52 
`A POSA would not have selected a maytansinoid to be
`conjugated with an anti-HER2 antibody because of the
`maytansinoid toxicity profile .............................................................. 55 
`Even if a POSA were to make an anti-HER2 immunoconjugate, that POSA
`would not have had reason to select Herceptin® ......................................... 59 
`A. 
`Resistance to Herceptin® would have deterred a POSA from
`including it in an immunoconjugate .................................................... 60 
`
`X. 
`
`
`
`2
`
`C. 
`
`B. 
`
`C. 
`
`IMMUNOGEN 2134, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`
`B. 
`
`C. 
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Herceptin®’s status as a humanized antibody does not
`provide a reason to include it in an immunoconjugate ....................... 64 
`Herceptin®’s high affinity binding and approval as an
`independent agent do not provide a reason to include it in an
`immunoconjugate ................................................................................ 69 
`XI.  Combination therapy prior art did not provide evidence of the obviousness
`of immunoconjugates.................................................................................... 70 
`XII.  A POSA would not have had a reason conjugate Herceptin® to a
`maytansinoid because of their incompatible mechanisms of action ............ 74 
`XIII.  A POSA would not have had any reasonable expectation of success in
`making an immunoconjugate that treated solid tumors in humans .............. 80 
`A.  A POSA would have been aware that creating successful
`immunoconjugates was very difficult ................................................. 83 
`A POSA would not have reasonably expected the claimed
`immunoconjugates to succeed because no immunoconjugate
`had ever succeeded in treating solid tumors ....................................... 87 
`XIV.  A POSA would not have chosen a noncleavable linker ............................... 90 
`A. 
`Release of a maytansinoid from an antibody is essential for
`activity of a maytansinoid-based immunoconjugate ........................... 91 
`Researchers in the field would not have selected the non-
`cleavable SMCC linker in making maytansinoid-based
`immunoconjugates............................................................................... 94 
`Researchers would have
`expected
`that
`linking
`a
`maytansinoid to Herceptin via the non-cleavable SMCC
`linker would produce an inactive immunoconjugate .......................... 96 
`XV.  Objective evidence supports the nonobviousness of the claims ................ 105 
`A. 
`T-DM1 is unexpectedly superior to the SMCC linker
`immunoconjugate in Chari 1992 .......................................................105 
`T-DM1 is unexpectedly superior to the immunoconjugate in
`Chari 1992 with a cleavable linker ....................................................109 
`XVI.  Conclusion .................................................................................................. 111 
`APPENDIX A ....................................................................................................... 114 
`APPENDIX B ....................................................................................................... 116 
`
`B. 
`
`B. 
`
`C. 
`
`B. 
`
`
`
`3
`
`IMMUNOGEN 2134, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`
`
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`I, Geoffrey A. Pietersz, hereby declare as follows.
`
`I.
`
`Introduction
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of ImmunoGen,
`
`Inc., (“ImmunoGen”) for the above-captioned inter partes review (IPR). I am
`
`being compensated for my time in connection with this IPR at my standard
`
`consulting rate of $350 per hour. I have no personal or financial interest in the
`
`outcome of this proceeding.
`
`3.
`
`I understand that the petition for inter partes review involves U.S.
`
`Patent No. 8,337,856 (“the ’856 patent”) (Ex. 1001), the application for which was
`
`filed on December 3, 2007, naming Walter Blättler and Ravi V.J. Chari as the
`
`inventors. I understand that, because the ’856 patent was the result of a series of
`
`related applications, the earliest possible priority date of the ’856 patent is March
`
`16, 2000. In my analysis, I have considered the state of the art and what a person of
`
`ordinary skill in the art would have understood prior to March16, 2000. I further
`
`understand that, according to the USPTO records, the ’856 patent is currently
`
`
`
`4
`
`IMMUNOGEN 2134, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IPR2014-00676
`
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`assigned to ImmunoGen. Finally, I understand that the petitioner in this inter
`
`
`
`partes review is Phigenix, Inc. (“Phigenix”).
`
`4.
`
`In formulating my opinions, I have relied upon my experience,
`
`education and knowledge in the relevant art. In formulating my opinions, I have
`
`also considered the viewpoint of a person of ordinary skill in the art (“POSA”)
`
`(i.e., a person of ordinary skill in the field of immunoconjugates, defined further
`
`below in Section IV) prior to March 16, 2000.
`
`II. My background and qualifications
`5.
`I am an expert in the fields of immunoconjugates and antibody-
`
`targeted therapeutics. Since 2006, I have been a Senior Principal Research Fellow
`
`at the Burnet Institute, as well as a full professor both at the University of
`
`Melbourne and Monash University. Further, I have been a Director of Technology
`
`Development for Ascend Biopharmaceuticals Ltd. since 2013. Before accepting
`
`these positions, I was a research fellow at the Austin Research Institute in
`
`Heidelberg, Victoria (1991-2006), a senior research chemist at Arthron Ltd. (2001-
`
`2003), and a research fellow at the University of Melbourne (1982-1991). I
`
`received both my B.Sc. (Hons) and Ph.D. in organic chemistry from the University
`
`of Melbourne in 1978 and 1982, respectively.
`
`
`
`5
`
`IMMUNOGEN 2134, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`As a result of my research studies, I have published over 165 papers in
`
`6.
`
`
`
`peer reviewed journals. I have more than 25 years of experience with monoclonal
`
`antibodies, immunoconjugates, and vaccines, including their characterization and
`
`measurement of anti-tumor efficacy. I also have expertise in recombinant
`
`antibodies and animal models of cancer and infectious disease. I have developed
`
`many novel methods for conjugating drugs to monoclonal antibodies, including
`
`methods of using both cleavable and non-cleavable linkers. I have also carried out
`
`a Phase I/II study of an immunoconjugate.
`
`7.
`
`As a result of my research efforts, I have been awarded numerous
`
`patents, including multiple patents for immunoconjugates that target tumors. I have
`
`served as a reviewer for numerous international grant bodies, and have been a
`
`member of the editorial board of several scientific journals, including that of
`
`Bioconjugate Chemistry from 1990 to 1996. I have also had many teaching roles in
`
`my career, teaching undergraduate, graduate and medical students various subjects
`
`related to immunoconjugates. Finally, my expertise is reflected in my having been
`
`asked to serve as a consultant for six separate biomedical research companies.
`
`8.
`
`Accordingly, I am an expert in the fields of immunoconjugates and
`
`antibody-targeted therapeutics. My full background is detailed in my curriculum
`
`vitae. (Ex. 2135.)
`
`
`
`6
`
`IMMUNOGEN 2134, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`III. List of documents I considered in formulating my opinions
`9.
`In preparing this Declaration, I have reviewed the ’856 patent,
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Phigenix’s Petition for Inter Partes review of U.S. Patent No. 8,337,856 (Paper 5),
`
`ImmunoGen’s Patent Owner Preliminary Response (Paper 10), and the Institution
`
`Decision (Paper 11). I have also considered the scientific publications cited therein,
`
`in light of general knowledge in the art. In formulating my opinions, I
`
`have considered all the references cited in this declaration, including those listed
`
`below, in light of the general knowledge in the art.
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`
`Description
`Exhibit No.
`Ex. 1001 U.S. Patent No. 8,337,856 (Blӓttler, et al.).
`Slamon, et al., “Studies of the HER-2/neu protooncogene in human
`Ex. 1002
`breast and ovarian cancer.” Science 244:707-712 (1989).
`Press, et al., “HER-2/neu gene amplification characterized by
`fluorescence in situ hybridization: poor prognosis in node-negative
`breast carcinomas.” J. Clin. Oncol. 15:2894-2904 (1997).
`Phillips, et al., “Targeting HER2-positive breast cancer with
`trastuzumab-DM1, an antibody-cytotoxic drug conjugate.” Cancer
`Res. 68: 9280-9290 (2008).
`Hudziak, et al., “p185HER2 monoclonal antibody has antiproliferative
`effects in vitro and sensitizes human breast tumor cells to tumor
`necrosis factor.” Mol. Cell. Biol., 9:1165-1172 (1989).
`McKenzie, et al., “Generation and characterization of monoclonal
`antibodies specific for the human neu oncogene product, p185.”
`Oncogene, 4:543-548 (1989).
`Ring, et al., “Identity of BCA200 and c-erbB-2 indicated by
`reactivity of monoclonal antibodies with recombinant c-erbB-2.”
`Mol. Immunol., 28:915-917 (1991).
`Ex. 1008 HERCEPTIN® Label.
`Ex. 1009 Blythman, et al., “Immunotoxins: hybrid molecules of monoclonal
`antibodies and a toxin subunit specifically kill tumour cells.”
`
`Ex. 1006
`
`Ex. 1007
`
`
`
`7
`
`IMMUNOGEN 2134, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`Exhibit No.
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Description
`Nature, 290:145-146 (1981).
`Ex. 1010 Vitetta, et al., “Monoclonal antibodies as agonists: an expanded role
`for their use in cancer therapy.” Cancer Res., 54:5301-5309 (1994).
`Maier, et al., “Requirements for the internalization of a murine
`monoclonal antibody directed against the HER-2/neu gene product
`c-erbB-2.” Cancer Res., 51: 5361-5369 (1991).
`Chari, et al., “Immunoconjugates containing novel January 1,
`maytansinoids: promising anticancer drugs.” Cancer Res., 52:127-
`131 (1992).
`Batra, et al., “Recombinant anti-erbB2 immunotoxins containing
`Pseudomonas exotoxin.” Proc. Natl. Acad. Sci., USA, 89:5867-5871
`(1992).
`Liu, et al., “The development of antibody delivery systems to target
`cancer with highly potent maytansinoids.” Exp. Opin. Invest. Drugs,
`6: 169-172 (1997).
`Ex. 1015 Chari, “Targeted delivery of chemotherapeutics: tumor-activated
`prodrug therapy.” Adv. Drug Del. Rev., 31: 89-104 (1998).
`Ex. 1016 Declaration of Michael G. Rosenblum, Ph.D.
`Ex. 1017 U.S. Patent No. 5,770,195 (Hudziak, et al.).
`Rosenblum, et al., “Recombinant immunotoxins directed against the
`c-erbB-2/HER2/neu oncogene product: in vitro cytotoxicity,
`pharmacokinetics, and in vivo efficacy studies in xenograft
`models.” Clin. Cancer Res., 5:865-874 (1999).
`Baselga, et al., “Recombinant humanized anti-HER2 antibody
`(Herceptin ™) enhances the antitumor activity of paclitaxel and
`doxorubicin against HER2/neu overexpressing human breast cancer
`xenografts.” Cancer Res., 58:2825-2831 (1998).
`Pegram, et al., “Inhibitory effects of combinations of HER-2/neu
`antibody and chemotherapeutic agents used for treatment of human
`breast cancers.” Oncogene, 18:2241-2251 (1999).
`Morgan, et al., “Immunotoxins of Pseudomonas exotoxin A (PE):
`effect of linkage on conjugate yield, potency, selectivity and
`toxicity.” Mol. Immunol. 27:273-282 (1990).
`Carter, et al., “Humanization of an anti-p 185HER2 antibody for
`human cancer therapy.” Proc. Natl. Acad. Sci., USA, 89:4285-4289
`(1992).
`Liu, et al., “Eradication of large colon tumor xenografts by targeted
`
`Ex. 1011
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1018
`
`Ex. 1019
`
`Ex. 1020
`
`Ex. 1021
`
`Ex. 1022
`
`Ex. 1023
`
`
`
`8
`
`IMMUNOGEN 2134, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`Exhibit No.
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Description
`delivery of maytansinoids.” Proc. Natl. Acad. Sci., USA, 93:8618-
`8623 (1996).
`Ex. 1024 U.S. Patent No. 5,208,020 (Chari, et al.).
`Ex. 1025 Cohen, “Treatment With Anti-ErbB2 Antibodies,” U.S. Pre-Grant
`Publication No. 2003/0170235.
`Ex. 1026 Declaration of Walter Blӓttler and Ravi Chari filed on September
`11, 2012, in U.S. Application No. 11/949,351.
`Ex. 1027 Response to Office Action of June 8, 2010, filed on July 6, 2010, in
`U.S. Application No. 11/949,351.
`Ex. 1028 Declaration by Mark X. Sliwkoswki, Ph.D., filed on July 6, 2010, in
`U.S. Application No. 11/949,351.
`Ex. 1029 Declaration by Barbara Klencke, M.D. , filed on July 6, 2010, in
`U.S. Application No. 11/949,351.
`Suzuki, et al., “Immunoselective cell growth inhibition by antibody-
`Adriamycin conjugates targeting c-erbB2 product on human cancer
`cells.” Biol. Pharm. Bull. 18:1279-1282 (1995).
`Drewinko, et al., “Differential killing efficacy of twenty antitumor
`drugs on proliferating and nonproliferating human tumor cells.”
`Cancer Res. 41:2328-2333 (1981).
`Ex. 1032 Curriculum vitae of Michael G. Rosenblum, Ph.D.
`Maytansine, Annual Report to the Food and Drug Administration;
`Investigational Drug Branch Cancer Therapy Evaluation Program
`Division of Cancer Treatment National Cancer Institute, 1-21
`(1984).
`Ex. 2003 Cabanillas, F., et al., "Results of a Phase II Study of Maytansine in
`Patients with Breast Carcinoma and Melanoma," Cancer Treatment
`Reports 63: 507-509 (1979).
`Ravry, M., et al., “Phase II Evaluation of Maytansine (NSC 153858)
`in Advanced Cancer,” American Journal of Clinical Oncology:
`Cancer Clinical Trials 8: 148-150 (1985).
`Ex. 2006 Blättler, W., et al., “Immunoconjugates,” in Cancer Therapeutics:
`Experimental and Clinical Agents, Chapter 17, pp. 371-394 (1996).
`Dubowchik, G. and Walker, M.A., “Receptor-Mediated and
`Enzyme-Dependent Targeting of Cytotoxic Anticancer Drugs,”
`Pharmacology & Therapeutics 83: 67-123 (1999).
`Tolcher, A., et al., “Randomized Phase II Study of BR96-
`Doxorubicin Conjugate in Patients With Metastatic Breast Cancer,”
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 2002
`
`Ex. 2005
`
`Ex. 2007
`
`Ex. 2010
`
`
`
`9
`
`IMMUNOGEN 2134, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`Exhibit No.
`
`Ex. 2011
`
`Ex. 2016
`
`Ex. 2017
`
`Ex. 2029
`
`Ex. 2030
`
`Ex. 2031
`
`Ex. 2032
`
`Ex. 2033
`
`Ex. 2034
`
`Ex. 2035
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Description
`Journal of Clinical Oncology 17: 478-484 (1999).
`Elias, D., et al., “Monoclonal Antibody KS1/4-Methotrexate
`Immunoconjugate Studies in Non-Small Cell Lung Carcinoma,”
`American Journal of Respiratory and Critical Care Medicine 150:
`1114-1122 (1994).
`Cao, Y., and Rosenblum, M.G., "Design, Development, and
`Characterization of Recombinant Immunotoxins Targeting
`HER2/neu," in Antibody-Drug Conjugates and Immunotoxins: From
`Pre-Clinical Development to Therapeutic Applications, Chapter 18,
`pp. 319-348 (2013).
`Engert, A., et al., “The Emerging Role of Ricin in A-Chain
`Immunotoxins in Leukemia and Lymphoma” in Clinical
`Applications of Immunotoxins by Frankel, A.E., (Ed.), pp. 1-23
`(1998).
`Pai-Scherf, L., et al., “Hepatotoxicity un Cancer Patients Receiving
`erb-38, a Recombinant Immunotoxin That Targets the erbB2
`Receptor,” Clinical Cancer Research 5: 2311-2315 (1999).
`Pai, L., et al., “Clinical Evaluation of Intraperitoneal Pseudomonas
`Exotoxin Immunoconjugate OVB3-PE in Patients With Ovarian
`Cancer,” Journal of Clinical Oncology 9: 2095-2103 (1991).
`Gould, B., et al., “Phase I Study of an Anti-Breast Cancer
`Immunotoxin by Continuous Infusion: Report of a Targeted Toxic
`Effect Not Predicted by Animal Studies,” Journal of the National
`Cancer Institute 81: 775-781 (1989).
`Drebin, J., et al., “Monoclonal antibodies specific for the neu
`Oncogene Product Directly Mediate Anti-Tumor Effects in vivo,”
`Oncogene 2:387-394 (1988).
`Stancovski, I., et al., “Mechanistic Aspects of the Opposing Effects
`of Monoclonal Antibodies to the ERBB2 Receptor on Tumor
`Growth,” Proc. Natl. Acad. Sci. 88: 8691-8695 (1991).
`Kita, Y., et al., “ErbB Receptor Activation, Cell Morphology
`Changes, and Apoptosis Induced by Anti-Her2 Monoclonal
`Antibodies,” Biochemical and Biophysical Research
`Communications 226: 59-69 (1996).
`Klapper, L., et al., “A Subclass of Tumor-Inhibitory Monoclonal
`Antibodies to ErbB-2/HER2 Blocks Crosstalk with Growth Factor
`Receptors,” Oncogene 14: 2099-2109 (1997).
`
`
`
`10
`
`IMMUNOGEN 2134, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`Exhibit No.
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Description
`Xu, F., et al., “Antibody-Induced Growth Inhibition Is Mediated
`Through Immunochemically and Functionally Distinct Epitopes on
`the Extracellular Domain of the c-erb B-2 (HER-2/neu) Gene
`Product p185,” Int. J. Cancer 53: 401-408 (1993).
`Rodriguez, G., et al., “The Effect of Antibodies and Immunotoxins
`Reactive with HER-2/neu on Growth of Ovarian and Breast Cancer
`Cell Lines,” Am J of Obstet Gynecol 168: 228-232 (1993).
`Boyer, C., et al., “Relative Cytotoxic Activity of Immunotoxins
`Reactive With Different Epitopes on the Extracellular Domain of the
`c-erbB-2 (HER-2/neu) Gene Product p185,” Int. J. Cancer 82: 525-
`531 (1999).
`Ex. 2039 Deposition Transcript of Michael G. Rosenblum, Ph.D., Vol. I.
`Ex. 2040 Deposition Transcript of Michael G. Rosenblum, Ph.D., Vol. II.
`Zimmerman, H.J., “Hepatotoxic Effects of Oncotherapeutic and
`Immunosuppressive Agents,” in Hepatotoxicity The Adverse Effects
`of Drugs and Other Chemicals on the Liver, Chapter 23, pp. 673-
`708 (1999).
`Eagan, R.T., et al., “Early Clinical Study of an Intermittent Schedule
`for Maytansine (NSC-153858): Brief Communication,” J Natl
`Cancer Inst 60: 93-96 (1978).
`Issell, B., and Crooke, S., “Maytansine,” Cancer Treatment Reviews
`Ex. 2043
`5: 199-207 (1978).
`Ex. 2044 Cabanillas, F., et al., “Phase I Study of Maytansine Using a 3-Day
`Schedule,” Cancer Treatment Rep 62: 425-428 (1978).
`Rosenblum, M., et al., “A Specific and Potent Immunotoxin
`Composed of Antibody ZME-018 and the Plant Toxin Gelonin,”
`Mol Biother 3: 6-13 (1991).
`Reiter, Y., et al., “Improved Binding and Antitumor Activity of a
`Recombinant Anti-erbB2 Immunotoxin by Disulfide Stabilization of
`the Fv Fragment,” The Journal of Biological Chemistry 269: 18327-
`18331 (1994).
`Ex. 2047 U.S. Patent No. 7,754,211 to Rosenblum et al (filed on October 13,
`2004; issued on July 13, 2010).
`Christianson, T., et al., “NH2 –terminally Truncated HER-2-neu
`Protein: Relationship with Shedding of the Extracellular Domain
`and with Prognostic Factors in Breast Cancer,” Cancer Research 58:
`5123-5129 (1998).
`
`Ex. 2036
`
`Ex. 2037
`
`Ex. 2038
`
`Ex. 2041
`
`Ex. 2042
`
`Ex. 2045
`
`Ex. 2046
`
`Ex. 2048
`
`
`
`11
`
`IMMUNOGEN 2134, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`
`
`
`Exhibit No.
`
`Ex. 2049
`
`Ex. 2050
`
`Ex. 2051
`
`Description
`Sliwkowski, M., et al., “Nonclinical Studies Addressing the
`Mechanism of Action of Trastuzumab (Herceptin),” Seminars in
`Oncology 26: 60-70 (1999).
`Zabrecky, J., et al., “The Extracellular Domain of p185/neu Is
`Released from the Surface of Human Breast Carcinoma Cells, SK-
`BR-3,” The Journal of Biological Chemistry 266: 1716-1720 (1991).
`Kwong, K.Y., and Hung, M., “A Novel Splice Variant HER2 With
`Increased Transformation Activity,” Molecular Carcinogenesis 23:
`62-68 (1998).
`Ex. 2052 U.S. Patent No. 5,783,404 to Koski, R., (filed Apr. 13, 1995, issued
`July 21, 1998).
`Sorbera, L.A., and Rabasseda, X., “Trastuzumab,” Drugs of the
`Future 23: 1078-1082 (1998).
`Mountain, A., and Adair, J.A., “Engineering Antibodies for
`Therapy,” Biotechnology and Genetic Engineering Review 10: 1-
`142 (1992).
`Park, J., et al., “Biological Therapy of Breast Cancer,” BioDrugs 14:
`221-246 (2000).
`Tokuda, Y., et al., “Dose Escalation and Pharmacokinetic Study of a
`Humanized anti-HER2 Monoclonal Antibody in Patients with
`HER2/neu-Overexpressing Metastatic Breast Cancer,” British
`Journal of Cancer 81: 1419-1425 (1999).
`Wilson, L., et al., Modulation of Microtubule Dynamics by Drugs:
`A Paradigm for the Actions of Cellular Regulators,” Cell Structure
`and Function 24: 329-335 (1999).
`Wels, W., et al., “Construction, Bacterial Expression and
`Characterization of a Bifunctional Single-Chain Antibody-
`Phospatase Fusion Protein Targeted to the Human ERBB-2
`Receptor,” Biotechnology 10: 1128-1132 (1992).
`Tecce, R., et. al., “Characterization of Cytotoxic Activity of Saporin
`Anti-GP185/HER-2 Immunotoxins,” Int. J. Cancer 55: 122-127
`(1993).
`Maurer-Gebhard, M., et al., “Systemic Treatment with a
`Recombinant erbB-2 Receptor-specific Tumor Toxin Efficiently
`reduces Pulmonary Metastases in Mice Injected with Genetically
`Modified Carcinoma Cells,” Cancer Research 58: 2661-2666
`(1998).
`
`Ex. 2053
`
`Ex. 2056
`
`Ex. 2057
`
`Ex. 2058
`
`Ex. 2059
`
`Ex. 2061
`
`Ex. 2063
`
`Ex. 2065
`
`
`
`12
`
`IMMUNOGEN 2134, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`
`
`
`Exhibit No.
`
`Ex. 2066
`
`Description
`Beerli, R., et al., "Intracellular expression of Single Chain
`Antibodies Reverts ErbB-2 Transformation," The Journal of
`Biological Chemistry 269: 23931-23936 (1994).
`Wels, W., et al., "EGF Receptor and p185erbB-2 –Specific Single-
`Chain Antibody Toxins Differ in Their Cell-Killing Activity on
`Tumor Cells Expressing Both Receptor Proteins," Int. J. Cancer 60:
`137-144 (1995).
`Hancock, M.C., et al., "A Monoclonal Antibody Against the c-erbB-
`2 Protein Enhances the Cytotoxicity of cis-
`Diamminedichloroplatinum Against Human Breast and Ovarian
`Tumor Cell Lines," Cancer Research 51: 4575-4580 (1991).
`Liu, H., et al., "Construction of a Chimeric Antibody with
`Therapeutic Potential for Cancers Which Overexpress c-erbB-2,"
`Biochemical and Biophysical Research Communication 211: 792-
`803 (1995).
`Drebin, J., et al., "Down-Modulation of an Oncogene Protein
`Product and Reversion of the Transformed Phenotype by
`Monoclonal Antibodies," Cell 41: 697-706 (1985).
`Drebin, J., et al., "Inhibition of Tumor Growth By a Monoclonal
`Antibody Reactive with an Oncogene-Encoded Tumor Antigen,"
`Proc. Natl. Acad. Sci 83: 9129-9133 (1986).
`Sedlacek, H., et al., “Antibodies as Carriers of Cytotoxicity,” in
`Ex. 2074
`Contributions to Oncology Vol. 43 (1992).
`Ex. 2075 U.S. Patent No. 7,083,957 to Rosenblum et al., (filed February 12,
`2002; issued August 1, 2006).
`Carroll, S., et al., Enhanced Stability in Vitro and in Vivo of
`Immunoconjugates Prepared with 5-Methyl-2-iminothiolane,”
`Bioconjugate Chem. 5: 248-256 (1994).
`Trouet, A., et al., “A Covalent Linkage Between Daunorubicin and
`Proteins That is Stable in Serum and Reversible by Lysosomal
`Hydrolases, As Required for a Lysosomotropic Drug-Carrier
`Conjugate: In Vitro and In Vivo Studies,” Proc. Natl. Acad. Sci. 79:
`626-629 (1982).
`Dosio, F., et al., “Role of Cross-Linking Agents in Determining the
`Biochemical and Pharmacokinetic Properties of Mgr6-Clavin
`Immunotoxins,” Bioconjugate Chem. 9: 372-381 (1998).
`Ex. 2079 Brinkley, M., "A Brief Survey of Methods for Preparing Protein
`
`Ex. 2067
`
`Ex. 2068
`
`Ex. 2069
`
`Ex. 2070
`
`Ex. 2071
`
`Ex. 2076
`
`Ex. 2077
`
`Ex. 2078
`
`
`
`13
`
`IMMUNOGEN 2134, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`
`
`
`Exhibit No.
`
`Ex. 2080
`
`Description
`Conjugates with Dyes, Haptens, and Cross-Linking Reagents,"
`Bioconjugate Chem. 3: 2-13 (1992).
`Schnell, R., et al., "Clinical Trials With an Anti-CD25 Ricin A-
`Chain Experimental and Immunotoxin (RFT5-SMPT-dgA) in
`Hodgkin's Lymphoma," Leukemia and Lymphoma 30: 525-537
`(1998).
`Ex. 2081 Delprino, L., et al., "Toxin-Targeted Design for Anticancer Therapy.
`II: Preparation and Biological Comparison of Different Chemically
`Linked Gelonin-Antibody Conjugates," Journal of Pharmaceutical
`Sciences 82: 699-704 (1993).
`Ex. 2082 Goff, D. A., and Carroll, S.R., "Substituted 2-Iminothiolanes:
`Reagents for the Preparation of Disulfide Cross-Linked Conjugates
`with Increased Stability," Bioconjugate Chem. 1: 381-386 (1990).
`“PDL's Humanized Antibody Technology, available at
`https://web.archive.org/web/20000303232942/http://www.pdl.com/
`Guid... (last accessed December 28, 2014).
`Campbell, A., “Intellectual Property: Exploration of Intellectual
`Property, Technology Transfer Through the MRC,” available at
`http://sciencecareers.sciencemag.org/career_magazine/previous_issu
`es/art... (last accessed December 28, 2014).
`Altenschmidt, U., et al., "Targeted Therapy of Schwannoma Cells in
`Immunocompetent Rats With an erbB2-Specific Antibody-Toxin,"
`Int. J. Cancer 73: 117-124 (1997).
`Ex. 2086 Horak, E., et al., "Radioimmunotherapy Targeting of HER2/neu
`Oncoprotein on Ovarian Tumor Using Lead-212-DOTA-AEI," J
`Nucl Med. 38: 1994-1950 (1997).
`Ex. 2087 Greenfield, L., et al., "Thiol-Containing Cross-Linking Agent with
`Enhanced Steric Hindrance," Bioconjugate Chem. 1: 400-410
`(1990).
`Thorpe, P., et al., "New Coupling Agents for the Synthesis of
`Immunotoxins Containing a Hindered Disulfide Bond with
`Improved Stability in Vivo," Cancer Research 47: 5924-5931
`(1987).
`Laguzza, B., et al., "New Antitumor Monoclonal Antibody-Vinca
`Conjugates LY203725 and Related Compounds: Design,
`Preparation, and Representative in Vivo Activity 1," J. Med. Chem
`32: 548-555 (1989).
`
`Ex. 2083
`
`Ex. 2084
`
`Ex. 2085
`
`Ex. 2088
`
`Ex. 2089
`
`
`
`14
`
`IMMUNOGEN 2134, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`Exhibit No.
`
`Ex. 2090
`
`Ex. 2091
`
`Ex. 2093
`
`Ex. 2094
`
`Ex. 2097
`
`Ex. 2098
`
`Ex. 2099
`
`Ex. 2109
`
`Ex. 2111
`
`Ex. 2112
`
`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`Description
`Braslawsky, G., et al., “Adriamycin (hydrazone)-antibody
`conjugates require internalization and intracellular acid hydrolysis
`for antitumor activity,” Cancer Immunol Immunother 33: 367-374
`(1991).
`Masuho, Y., et al., “Importance of the Antigen-Binding Valency and
`the Nature of the Cross-Linking Bond in Ricin A-Chain Conjugates
`with Antibody,” J. Biochem 91: 1583-1591 (1982).
`Trail, P.A., et al., “Cure of Xenografted Human Carcinomas by
`BR96-Doxorubicin Immunoconjugates,” Science 261: 212-215
`(1993).
`Hinman, L., et al., “Preparation and Characterization of Monoclonal
`Antibody Conjugates of the Calicheamicins: A Novel and Potent
`Family of Antitumor Antibodies,” Cancer Research 53: 3336-3342
`(1993).
`Ogata, M., et al., “Processing of Pseudomonas Exotoxin by a
`Cellular Protease Results in the Generation of a 37,000-Da Toxin
`Fragment That is Translocated to the Cytosol,” The Journal of
`Biological Chemistry 265: 20678-20685 (1990).
`Lambert, J., et al., “Purified Immunotoxins That Are Reactive with
`Human Lymphoid Cells,” The Journal of Biological Chemistry,”
`260: 12035-12041 (1985).
`Edwards, D.C., et al., “A Comparison of the In Vitro and In Vivo
`Activities of Conjugates of Anti-Mouse Lymphocyte Globulin and
`Abrin,” Biochimica et Biophysica Acta 717: 272-277 (1982).
`Mathé, G., et al., “Experimental Medicine – Effect on Mouse
`Leukemia 1210 of a Combination by Means of Diazotization of
`Amethopterin and of y-Globulins from hamsters with this Leukemia
`by Means of Heterograft,” Academy of Science Reports 246: 1626-
`1628 (1958).
`Cao, Y., et al., “Construction and Characterization of Novel,
`Recombinant Immunotoxins Targeting the Her2/neu Oncogene
`Product: In vitro and In vivo Studies,” Cancer Res 69: 8987-8995
`(2009).
`Cao, Y., et al., "Single-Chain Antibody-Based Immunotoxins
`Targeting Her2/neu: Design Optimization and Impact of Affinity on
`Antitumor Efficacy and Off-target Toxicity," Mol Cancer Ther 11:
`143-153 (2011).
`
`
`
`15
`
`IMMUNOGEN 2134, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IPR2014-00676
`Declaration of Geoffrey A. Pietersz, Ph.D. (Exhibit 2134)
`
`
`
`
`
`
`
`Exhibit No.
`
`Ex. 2113
`
`Ex. 2115
`
`Ex. 2128
`
`Ex. 2129
`
`Ex. 2136
`
`Ex. 2137
`
`Description
`Lyu, M., et al., “Cell-Targeting Fusion Constructs Containing
`Recombinant Gelonin,” in Methods in Enzymology Chapter 8, pp.
`167-214 (2012).
`Kuan, C., et al., “Immunotoxins Containing Pseudomonas Exotoxin
`That Target LeY Damage Human Endothelial Cells in an Antibody-
`specific Mode: Relevance to Vascular Leak Syndrome,” Clinical
`Cancer Research 1: 1589-1594 (1995).
`Ducry, L., and Stump, B., "Antibody-Drug Conjugates: Linking
`Cytotoxic Payloads to Monoclonal Antibodies," Bioconjug Chem
`21: 5-13 (2010).
`Szöllösi, J., et al., “ERBB-2 (HER2/neu) Gene Copy Number,
`p185HER-2 Overexpression, and Intratumor Heterogeneity in Human
`Breast Cancer,” Cancer Research 55: 5400-5407 (1995).
`Sharkey, R., et al., “Targeted Therapy of Cancer: New Prospects for
`Antibodies and Immunoconjugates,” A Cancer J Clin 56: 226-243
`(2006).
`Byers, V.S., and Baldwin, R.W., “Therapeutic Strategies With
`Monoclonal Antibodies and Immunoconjugates,” Immunology 65:
`329-335 (1988).
`Panowski, S., et al., “Site-specific antibody drug conjugates for
`Ex. 2138
`cancer therapy,” mAbs 6: 34-45 (2014).
`Ex. 2139 Antignani, A., et al., “Immunotoxins: The Role of the Toxin,”
`Toxins 5: 1486-1502 (2013).
`Pietersz, G., et al., “Chemoimmunoconjugates for the Treatment of
`Cancer,” Advances in Immunocology 56: 301-387 (1994).
`“Monoclonal Antibody Production: A Report of the Committee on
`Methods of Producing Monoclonal Antibodies Institute for
`Laboratory Animal Research National Research Council,” pp. 1-47,
`National Academy Press (1999).
`McGraw, K., et al., “Characterization of Murine and Humanized
`Anti-CD33, Gelonin Immunotoxins Reactive Against Myeloid
`Leukemias,” Cancer Immunol Immunother 39: 367-374 (1994).
`Sjogren, H., et al., “Antitumor Activity of Carcinoma-Reactive
`BR96-Doxorubicin Conjugate against Human Carcinomas in
`Athymic Mice and Rats and Syngeneic Rat Carcinomas in
`Immunocompetent Rats,” Cancer Research